Balancing Speed And Safety: A Cross-Sectional Analysis Of The Us Food And Drug Administration’s Expanded Access And Expedited Development Programs

The US Food and Drug Administration (FDA) is responsible for protecting public health by ensuring the safety and efficacy of drugs and biologics. One challenge for the FDA is establishing a balance between timely new drug access and patient safety through rigorous trial evidence. In response to its evolving needs, the FDA has created several programs to promote earlier availability of certain drugs and biologics, such as those for serious or life-threatening conditions. Notably, the FDA’s expanded access program was developed to allow patients with life-threatening conditions to access investigational medicines outside clinical trials, and the Breakthrough Therapy Designation was developed to expedite the approval of drugs that may offer significant advantages over existing therapies. Our purpose was to quantitatively examine how these programs have affected the timing of drug access, and in the case of the Breakthrough Therapy designation, how it has affected the FDA’s approval standards. First, to study expanded access programs, we performed a cross-sectional analysis of expanded access programs registered through August 1, 2017 on ClinicalTrials.gov and identified key regulatory dates from publicly available FDA documents. Through ClinicalTrials.gov, 92 FDA-approved drugs and biologics with associated expanded access programs initiated prior to FDA approval were identified. The median (interquartile range [IQR]) premarket expanded access availability was 10.0 (6.0-19.5) months, constituting a median (IQR) of 14% (7%-25%) of the premarket clinical development period (investigational new drug application activation to FDA approval). Of 92 expanded access programs, 64 (69.6%) were initiated just before or after new drug application submission: 24 (26.1%) were initiated during the 6-month period before, and 40 (43.5%) in the 6 months after. Next, to study the Breakthrough Therapy Designation, we identified all FDA approvals granted the Breakthrough Therapy Designation from January 2012 through December 2017. For each new therapeutic, we abstracted key regulatory dates as well as pivotal trial data supporting its approval. From 2012 through 2017, the FDA approved 46 therapeutics with Breakthrough Therapy designation on the basis of 89 pivotal trials. The median number of pivotal trials per indication approval was 1 (IQR, 1-2), and the median number of patients enrolled among all pivotal trials supporting an indication approval was 222 (IQR, 124-796). Among these approvals, 27 were made on the basis of pivotal trials using randomization (58.7%), 21 using double-blind allocation (45.7%), 25 using an active or placebo comparator group (54.3%), and 10 using a clinical primary end point (21.7%). Our findings suggest that the FDA’s expanded access program generally provides access to investigational medicines late in clinical development when evidence of safety and effectiveness has been established. In addition, our findings show that drugs approved through Breakthrough Therapy Designation are often based on weak clinical trial evidence, informing patients and providers about the safety and efficacy of these drugs as well as the need for rigorous postmarketing studies

Additional file 2: of Biomarkers for the detection of renal fibrosis and prediction of renal outcomes: a systematic review

Methods of fibrosis assessment on biopsy in stage I studies. The table above shows the different methods used to assess fibrosis across different studies in stage I. Fibrosis was evaluated using Banff criteria, image digitalization, numerical quantification score, Oxford classification, morphometric analysis, Lee’s classification, chronic allograft damage index (CADI) score, and semi-quantitatively. (DOC 31 kb

Additional file 3: of Biomarkers for the detection of renal fibrosis and prediction of renal outcomes: a systematic review

Patient populations and renal outcomes assessed in stage I and stage II of the systematic review. The above table shows the heterogeneity in the data with varying patient populations and different operational definitions of worsening renal function. (DOC 43 kb

Biomarkers of inflammation and repair in kidney disease progression

INTRODUCTIONAcute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision making, more accurate information regarding risk of long-term progression to kidney failure is required.METHODSWe enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein 1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression.RESULTSHigher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis.CONCLUSIONSBiomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression.FUNDINGNIH

Valve-Related Hemodynamics Mediate Human Bicuspid Aortopathy: Insights From Wall Shear Stress Mapping

Suspected genetic causes for extracellular matrix (ECM) dysregulation in the ascending aorta in patients with bicuspid aortic valves (BAV) have influenced strategies and thresholds for surgical resection of BAV aortopathy. Using 4-dimensional (4D) flow cardiac magnetic resonance imaging (CMR), we have documented increased regional wall shear stress (WSS) in the ascending aorta of BAV patients. This study assessed the relationship between WSS and regional aortic tissue remodeling in BAV patients to determine the influence of regional WSS on the expression of ECM dysregulation. BAV patients (n = 20) undergoing ascending aortic resection underwent pre-operative 4D flow CMR to regionally map WSS. Paired aortic wall samples (i.e., within-patient samples obtained from regions of elevated and normal WSS) were collected and compared for medial elastin degeneration by histology and ECM regulation by protein expression. Regions of increased WSS showed greater medial elastin degradation compared to adjacent areas with normal WSS: decreased total elastin (p = 0.01) with thinner fibers (p = 0.00007) that were farther apart (p = 0.001). Multiplex protein analyses of ECM regulatory molecules revealed an increase in transforming growth factor β-1 (p = 0.04), matrix metalloproteinase (MMP)-1 (p = 0.03), MMP-2 (p = 0.06), MMP-3 (p = 0.02), and tissue inhibitor of metalloproteinase-1 (p = 0.04) in elevated WSS regions, indicating ECM dysregulation in regions of high WSS. Regions of increased WSS correspond with ECM dysregulation and elastic fiber degeneration in the ascending aorta of BAV patients, implicating valve-related hemodynamics as a contributing factor in the development of aortopathy. Further study to validate the use of 4D flow CMR as a noninvasive biomarker of disease progression and its ability to individualize resection strategies is warrante